Recent findings by Harper's group indicate that obstructive sleep apnea (OSA) is accompanied by brain damage in humans. It has been shown by Gozal's group that subjecting rats to levels of intermittent hypoxia similar to those seen in human OSA for 12h/day causes marked increases in apoptosis in CA1 hippocampus and neocortex, but not in CA3. Reduced expression of the NMDA NR1 glutamate receptor is also seen in CAl. These rats show long lasting cognitive deficits after their return to normoxic conditions. These deficits may be analogous to the persisting deficits commonly seen in human OSA patients after the apparently successful reversal of their sleep apnea. In prior studies, our group has shown that sleep deprivation under normoxic conditions leads to altered enzymatic activity in certain brain regions, consistent with the occurrence of oxidative stress. In the proposed studies we will test the hypothesis that chronic intermittent hypoxia (CIH) leads to changes in the activities of antioxidative enzymes and in the levels of free radical generated products and that these effects interact with the sleep disruption in OSA to produce cell damage. We will determine the time course and regional distribution of oxidative stress indicators under CIH. We have preliminary evidence showing increased activities of antioxidative enzymes under CIH. One of the principal means by which oxidative stress damages neurons is by excitotoxicity mediated by glutamate (and serotonin) release. We will use in vivo microdialysis to monitor the release of these neurotransmitters under CIH conditions and determine the time course of release with respect to sleep states. We hypothesize that CIH produces a larger increase in glutamate and serotonin release in waking than in nonREM sleep relative to normoxic conditions and that a portion of the damage in OSA is a result of this CIH interaction with periodic arousal. We will compare oxidative stress measures and neurotransmitter release in CA1 and CA3 to determine whether the relative resistance of CA3 to CIH is due to lower levels of oxidative stress or whether it results from a greater resistance of these neurons to comparable metabolic insult. We will determine if antioxidants and NMDA receptor blockers can protect against the detrimental effects of CIH under conditions of sleep disruption. These studies will clarify the dynamics underlying CIH induced brain damage and may facilitate the development of physiological and pharmacological approaches to minimize such damage in OSA.